Disubstituted xanthone carboxylic acid compounds

ABSTRACT

Compositions containing and methods employing, as the essential ingredient, novel disubstituted xanthone carboxylic acid compounds which are useful in the treatment of allergic conditions. Methods for preparing these compounds and compositions and intermediates therein are also disclosed. 5methylsulfinyl-7-isopropoxyxanthone-2-carboxylic acid and 5,7di(methylsulfinyl)xanthone-2-carboxylic acid are illustrated as representative compounds.

Mister et a1.

DKSUBSTITUTED XANTHONE @ARBOXYLIC ACID COMPOUNDS Inventors: Jul-g R. Pfister, Los Altos; llan '11.

Harrison; John H. Fried, both of Palo Alto, all of Calif.

Assignee: Syntex (USAJ ind, Palo Alto,

Calif.

Filed: Jan. 8, 1974.

Appl. No.: 431,794

Related US. Application Data Continuation-impart of Ser. No. 259,852, June 5, 1972, which is a continuation in-part of Ser. No. 217,287, Jan. 12, 1972, Pat. No. 3,849,565.

[ July 8, 1975 [56] lliefierences Cited UNITED STATES PATENTS 3,642,997 2/1972 Shen et al. .i 424/250 3,706,768 12/1972 Bays 260/335 Primary Examiner-Norma S. Milestone Attorney, Agent, or Firm-Gerard A. Blaufarb; Leon Simon; William E. Walker [5 7] ABSTRAT Compositions containing and methods employing, as the essential ingredient, novel disubstituted xanthone carboxylic acid compounds which are useful in the treatment of allergic conditions. Methods for preparing these compounds and compositions and intermediates therein are also disclosed. 5-methylsulfinyl-7- isopropoxyxanthone-Z-carboxylic acid and 5,7- di(methylsulfinyl)xanthone-Z-carboxylic acid are illustrated as representative compounds.

2 Claims, No Drawings DISUBSTKTU'KED XANTHONE CARBUXYLHC ACHD COMPOUNDS This application is a continuation-in-part of application Ser. No. 259,852, filed June 5, 1972, in turn a continuation-in-part of application Ser. No. 217,287, filed Jan. 12, l972 and now US. Pat. No. 3,849,565.

The present invention is directed to novel disubstituted xanthone carboxylic acid compounds and to compositions containing and methods utilizing these compounds as the essential ingredient in the treatment of symptoms associated with allergic manifestations, for example, asthmatic conditions.

In a first aspect, the present invention relates to novel C-5,7 disubstituted xanthone-Z-carboxylic acid compounds selected from those represented by the following formulas:

COOH

one R group is selected from alkyl and alkoxy andthe other R group is selected from lhydroxylower alkyl and the lower alkyl, cycloalkyl, tetrahydrofuran- 2-yl, tetrahydropyran-Z-yl, tetrahydropyran-4-yl and R nc NW coon llll.

MCI-OR 0 r ll 0 rU-s 4-alkoxytetrahydropyran-4-yl ethers thereof and the carboxylic acyl esters thereof; lower alkanoyl; and the group in which each of n and R is as defined above.

Thus included within the scope of the present invention are:

l. the C-5,7 disubstituted xanthone-Z-carboxylic acid compounds wherein the substituents are identical and as defined by R above, and

2. the C-5,7 disubstituted xanthone-Z-carboxylic acid compounds wherein the substituents are different and as defined by R above.

Those of class 1) include the 5,7-di( l-hydroxylower alkyl)xanthone-Z-carboxylic acid compounds and the lower alkyl, cycloalkyl, tetrahydrofuran-Z-yl, tetrahydropyran-2-yl, tetrahydropyran-4-yl and 4-alkoxytetrahydropyran-4-yl ethers (preferably methoxy) and esters (preferably acetoxy) thereof;

5,7-di(lower alkanoyl)xanthone-2-carboxylic acid compounds,

5,7-di(lower alkyl acid compounds,

5,7-di(lower alkyl acid compounds,

5,7di(sulfo)xanthone-Z-carboxylic acid compounds, 5,7-di(sulfamoyl)xanthone-Z-carboxylic acid compounds,

5,7-di(N-monolower alkyl sulfamoyl)xanthone-2- carboxylic acid compounds, and

5,7-di(N,N-dilower alkyl sulfamoyl)xanthone-2- carboxylic acid compounds, represented respectively by the following formulas A-l to A-6:

sulfinyl )xanthone-Z-carboxylic sulfonyl)xanthone-2carboxylic coon 9 ,coou R ..r coon o=s=o o 7 Q coon ozsizo N(R7) 2 A- 1 dropyran-4-yl, or carboxylic acyl containing up to 12 sentedbythe following? formulas:

3 4 and the pharmaceutically acceptable, non-toxic esters, This aspect of the present invention thus relates to a amides, and salts thereof; wherein R is hydrogen, method u's eful for inhibiting the effe'cts of the allergic lower alkyl, cycloalkyl, tetrahydrofuran-Z-yl, tetrahyreactionnw hich comprises administering an effective dropyran-Z-yl, tetrahydropyran-4-yl, 4-alkoxytetrahyamountof a conipound selected from those reprecarbon atoms; and each R each R each R and each R is lower alkyl and each R is hydrogen or lower alkyl. Those of class 2) include the 5-alkyl-7-(R xanthone-Z-carboxylic acid compounds, 5-alkoxy-7- (R )-xanthone-2-carboxylic acid compounds, 7-alkyl- 5-(R )-xanthone-2-carboxylic acid compounds and 7- alkoxy-5-(R )-xanthone-2-carboxylic acid compounds, wherein R is l-hydroxylower alkyl and the lower alkyl, cycloalkyl, tetrahydrofuran-Z-yl, tetrahydropyran-Z-yl, tetrahydropyran-4-yl and 4-alkoxytetrahydropyran- 2 0 4-y'l ethers thereof and the carboxylic acyl esters R COOH thereof (preferably methoxy ether and acetoxy ester); lower alkanoyl; lower alkylsulfinyl; lower alkylsulfonyl;

and sulfo; sulfamoyl; N-monolower alkylsulfamoyl; or o N,N-dilower alkylsulfamoyl; represented respectively by the following formulas 8-1 to B-4. (B)

. o I A eon R coon R on L and the pharmaceutically acceptable, non-toxic esters, 40 and the pharmaceutically acceptable, non-toxic esters, amides, and salts thereof; wherein R is as defined amides, and salts thereof;

above, and each of R R R, and R is alkyl. wherein the R groups are identical and selected from In a second aspect, the present invention is directed l-hydroxylower alkyl and the lower alkyl, cycloalkyl,

to a method useful for relieving symptoms associated tetrahydrofuran-Z-yl, tetrahydropyran-Z-yl, tetrahydrowith allergic manifestations such as are brought about pyran-4-yl and 4-alkoxytetrahydropyran-4-yl ethers by antigen-antibody (allergic) reactions. in the relief of thereof and the carboxylic acyl esters thereof; lower althese symptoms, the method hereof serves to inhibit kanoyl; and the group the effects of theallergic reaction when administered in an effective amount. While not intending to be bound by any theoretical mechanism of action, the

methodhereof is believed to operate by inhibiting the R release and/or the action of toxic products,'e.g. histamine, S-hydroxytryptamine, slow releasing substance (SRS-A), and others, which are produced as a result of in which n is the integer 1 or R is lower alkyl when a combination of specific antibody and antigen (allern is 1 and R is lower alkyl, y y amino, monolowef gic reaction). These properties make the subject comalkylamino, dilower alkylamino when n is and pounds particularly useful in the treatment of various one R2 group is selected from alkyl and alkoxy and all ic diti the other R group is selected from l-hydroxylower The compounds of the present invention are also alkyl and the lower alkyl, cycloalkyl, tetl'ahydrofuran' smooth muscle relaxants, e.g. bronchial dilaters, and -3 t y r yr n-Z-yI, tetrahydropyran-4-yl and are therefore useful in the treatment of conditions in -akl0xytetrahydropyran-4-yl ethers thereo and h which such agents may beindicated, as for instance, in carboxylic cy esters thereof; loWef lkanoyl, and the the treatment of broncho-constriction. The compounds I g p in which each ofn and R is as defined above; or a pharmaceutically acceptable non-toxic composition incorporating said acids, esters, amides or salts as an essential ingredient.

The present invention, in a third aspect, is directed to pharmaceutical compositions useful for inhibiting the effects of the allergic reaction comprising an effective amount of a compound selected from those represented by the following formulas:

and the pharmaceutically acceptable, non-toxic esters, amides, and salts thereof;

wherein the R groups are identical and selected from l-hydroxylower alkyl and the lower alkyl, cycloalkyl, tetrahydrofuran-Z-yl, tetrahydropyran-Z-yl, tetrahydropyran-4-yl and 4-alkoxytetrahydropyran-4-yl ethers thereof and the carboxylic acyl esters thereof; lower alkanoyl, and the group in which n is the integer l or 2, R is lower alkyl when n is l and R is lower alkyl, hydroxy, amino, monolower alkylamino, or dilower alkylamino when n is 2; and

one R group is selected from alkyl and alkoxy and the other R group is selected from l-hydroxylower alkyl and the lower alkyl, cycloalkyl, tetrahydrofuran- 2-yl, tetrahydropyran-Z-yl, tetrahydropyran-4-yl and 4-alkoxytetrahydropyran-4-yl ethers thereof and the carboxylic acyl esters thereof; lower alkanoyl, and the group in which each of n and R is as defined above; in admixture with a pharmaceutically acceptable non-toxic carrier.

In the practice of the method of the present invention, an effective amount ofa compound of the present invention or pharmaceutical compositions thereof, as defined above, is administered via any of the usual and acceptable methods known in the art, either singly or in combination with another compound or compounds of the present invention or other pharmaceutical agents, such as antibiotics, hormonal agents, and so forth. These compounds or compositions can thus be administered orally, topically, parenterally, or by inhalation and in the form of either solid, liquid, or gaseous dosages including tablets, suspensions, and aerosols, as discussed in more detail hereinafter. The administration can be conducted in single unit dosage form with continuous therapy or in single dose therapy ad libitum. ln the preferred embodiments, the method of the present invention is practiced when relief of symptoms is specifically required, or, perhaps, imminent; however, the method hereof is also usefully practiced as continuous or prophylactic treatment.

in view of the foregoing as well as in consideration of the degree or severity of the condition being treated, age of subject, and so forth, all of which factors being determinable by routine experimentation by one skilled in the art; the effective dosage in accordance herewith can vary over a wide range. Generally, an effective amount ranges from about 0.005 to about mg. per kg. of body weight per day and preferably from about 0.01 to about 100 mg. per kg. of body weight per day. ln alternate terms, an effective amount in accordance herewith generally ranges from about 0.5 to about 7000 mg. per day per subject.

Useful pharmaceutical carriers for the preparation of the compositions hereof, can be solids, liquids, or gases. Thus, the compositions can take the form of tablets, pills, capsules, powders, sustained release formulations, solutions, suspensions, elixirs, aerosols, and the like. The carriers can be selected from the various oils including those of petroleum, animal, vegetable, or synthetic origin, for example, peanut oil, soybean oil, mineral oil, sesame oil, and the like. Water, saline, aqueous dextrose, and glycols are preferred liquid carriers, particularly for injectable solutions. Suitable pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glyceryl monostearate, sodium chloride, dried skim milk, glycerol, propylene glycol, water, ethanol, and the like. Suitable pharmaceutical carriers and their formulation are described in Remingtons Pharmaceutical Sciences" by E. W. Martin. Such compositions will, in any event, contain an effective amount of the active compound together with a suitable amount of carrier so as to prepare the proper dosage form for proper administration to the host.

The compounds of the present invention demonstrate activity as inhibitors of the effects of the allergic reaction as measured by tests indicative of such activity involving passive cutaneous anaphylaxis as substantially described, for example, by J. Goose et al., Immunology, 16, 749 (1969).

Certain of the compounds of the present invention can be prepared in accordance with the following reaction sequence:

g c ucmco ll it 13 R138 (1) coon halo

COOR

wherein each of R and R is as above defined; halo is' bromo, chloro, fluoro, or iodo, preferably bromo; and' each of R and R" is lower alkyl, R being preferably methyl. v v I With reference to the above reaction sequence, an

ortho, para disubstituted (SR phenol (l) is condenscd with the l,3-dicarbo(lower)alkoxy-4 halobenzene compound (2) in the presence of cuprous oxide optionally inorganic liquid reaction medium,

. COOR' A SR13 coon preferably an organic amide such as dimethyl acetamide, dimethylformamide, N-methylpyrrolidone, tetramethylurea, and so forth, to prepare the corresponding 1 ,3-di'carbo( lower)alkoxy-4-( o,p-disubstituted 65 phenyloxy)-benzene compound (3).

The reaction is preferably conducted in an inert organic reaction medium, such as those listed above, or suitable mixtures of one ormoreof such media. The reaction is further conducted at temperatures ranging from about 80 to about 220C, preferably from abouot 120 to 200C, and for a period of time sufficient to complete the reaction, ranging from about two hours to about 24 hours.

The reaction consumes the reactants on the basis of one mole of the substituted phenol per mole of the dicarbo(lower)carboxyhalobenzene per half mole of cuprous oxide. However, the amounts of the reactants to be employed are not critical, some of the desired compound (3) being obtained when employing any proportions thereof. In the preferred embodiments, the reaction is conducted by reacting from about one to about three moles of the substituted phenol compound with about from one to about 1.2 moles of the dicarbo(lower)carboxyhalobenzene compound in the presence of from about 0.5 to about 0.6 moles of the cuprous oxide. The inert organic reaction medium, if employed, is used in solvent amounts.

Thereafter, the prepared compound (3) is base hydrolyzed to give the corresponding 1,3-dicarboxy-4- (o,p-disubstituted phenyloxy)-benzene (4). The base hydrolysis conditions can be any employed conventionally in the art. Generally, the hydrolysis reaction is conducted using an alkali metal hydroxide at about 50 to about 90C and for a period of time sufficient to complete the reaction, ranging from about 15 minutes to about 60 minutes, preferably in the presence of inert organic reaction media such as those normally employed in organic chemical reactions of this type, e.g. aqueous alkanol solutions. Although two moles of base are required per mole of compound (3), the amounts employed are not critical to produce the desired hydrolysis. Preferably from about three to about five moles of base are employed per mole of compound (3) and the reaction media, if employed, is used in solvent amounts.

The thus prepared diacid compound (4) is then cyclized with phosphoryl chloride, thionyl chloride, sulfuric acid, hydrogen fluoride, or, preferably, polyphosphoric acid (PPA), to give the corresponding 5,7- disubstituted xanthone-Z-carboxylic acid compound The reaction is preferably, but optionally, conducted in an inert organic reaction medium including those usually employed in organic chemical reactions, such as dimethylsulfoxide, sulfolane, benzene, toluene, and so forth. The reaction is further conducted at temperatures ranging from about 60 to about 180C, and for a period of time sufficient to complete the reaction ranging from about minutes to about 90 minutes.

Although the reaction consumes the reactants on the basis of one mole of compound (4) per mole cyclizing reagent, the reaction can be performed using any proportions of reactants. In the preferred embodiments, however, the reaction is conducted using from about to about 50 moles of the cyclizing reagent per mole of starting compound (4),

The 5,7-di(lower alkylthio)xanthone-2-carboxylic acid compounds (5) thus prepared are then esterified (R to give compounds (6) and the latter are oxidized followed by ester hydrolysis or compounds (5) are oxidized to give the 5,7-di-(lower alkylsulfinyl)- and 5,7- di(lower alkylsulfonyl)xanthone-2-carboxylic acid compounds (A-3) and (A4).

The esterification (5 6) is conducted with ethereal diazoalkane or with a lower alkanol in the presence ofa trace of sulfuric acid at reflux. Hydrolysis of the esters, if necessary, is conducted as described above for the conversion of compounds 3 4.

The oxidation of compounds 5 or 6 when conducted with a peracid, such as peracetic acid, mchloroperbenzoic acid, p-nitroperbenzoic acid, perphthalic acid, and so forth, yields the corresponding 5,7- di(lower alkylsulfinyl) acid compounds (A-3). The oxidation is preferably conducted in liquid reaction media such as a chlorinated hydrocarbon, e.g. chloroform, methylene chloride, and carbon tetrachloride. The reaction is conducted at temperatures ranging from about 10 to about 60C, preferably from about 0 to about 30C and for a period of time sufficient to complete the reaction, ranging from about one hour to about six hours. In the preferred embodiments, the reaction is conducted by reaction with from about 1 to about 1.1 moles of peracid,

Alternatively, the oxidation of compounds 5 or 6 with excess hydrogen peroxide gives the 5,7di(lower alkylsulfonyl) acid compounds (Ar-4). The peroxide oxidation is preferably conducted in liquid reaction media such as a lower carboxylic acid, e.g. acetic acid and propionic acid. The reaction is further conducted at temperatures ranging from about 20 to about 100C, preferably from 80 to about 90C and for a period of time sufficient to complete the reaction, ranging from about 30 minutes to about 3 hours. In the preferred embodiments, the reaction is conducted by reaction of from about five to about ten moles of hydrogen peroxide per mole of starting compound.

In said oxidation steps, and particularly that employing peracid, a mixture of products (A-3) and (A-4) may be obtained. If obtained, the mixture can be conventionally separated, such as via chromatography, if desired, to isolate the respective oxidized products.

Certain of the compounds of the present invention can be prepared in accordance with the following reaction sequence:

Seguencc B OCH COOR Sequence B-Continued 9 B Coon coon no-s (s l t in N(R712 wherein each of halo, R and R is as above defined.

With reference to the above reaction sequence, the 5,7-dihydroxyxanthone-2-carboxylic acid esters (12) are prepared as described above in Sequence A for compounds 1 6 including the step (10 1 1) of hydrolyzing'the methyl ethers with hydrobromic or hydroiodic acid and acetic acid, preferably at temperatures of from about 100 to about 160C. Thereafter, compounds 12) are treated with a dialkylthiocarbamoyl chloride, such as dimethylthiocarbamoyl chloride, in the presence of base, such as an alkali metal hydride, and in organic liquid reaction media, preferably an organic amide such as those listed above with respect to reaction (1 2 3) to afford the products (13). The reaction is conducted at temperatures ranging from about 20 to about 100C, preferably from about 60 to about 80C and for a period of time sufficient to complete the reaction, ranging from about one hour to about six hours. In the preferred embodiments, the reaction is conducted by reaction of from about 2.2 to about 3.0 moles of dialkylthiocarbamoyl chloride per mole of compound (12).

The product compounds (13) are then rearranged by reaction at a temperature of from about 200 to about 250C, preferably from about 220 to about 230C, and for a period of time ranging from about one hour to about eight hours and in the presence of organic medium such as sulfolane, nitrobenzene, triethyleneglycol, and so forth, which is preferably employed in solvent amounts, to give compounds (14).

Compounds (14) are then converted to the corre sponding 5,7-dimercapto acid compounds (15) by base hydrolysis such as those described above for the preparation of compounds (4) from (3).

Compounds (15) are treated with excess chlorine R -cn I on cn fin under acidic conditions to afford compounds 16). This reaction is conducted employing a pH of about 1 by use of hydrochloric acid, optionally in acetic acid solution. The reaction is further conducted at temperatures ranging from about 20 to about 100C, preferably from 50 to about C and for a period of time sufficient to complete the reaction, ranging from about 2 hours to about 12 hours.

Compound (16) is then reacted with a base, such as alkali metal hydroxide, preferably under aqueous conditions and at a temperature ranging from about 20 to about 100C, preferably from to about C and for a period of from about one hour to about two hours and acidified to give the 5,7-disulfo-substituted acid compounds (A-5).

Compounds (16) can be treated with ammonia, monolower alkylamine, or dilower alkylamine to give the 5,7-disulfamoyl, -di(monolower alkyl)sulfamoyl, and -di(dilower alkyl)sulfamoyl acid compounds (A-6). This reaction is conducted at temperatures ranging from about 0 to about 80C, preferably from 20 to about 30C, and for a period of time sufficient to complete the reaction, ranging from about one hour to about eight hours. In the preferred embodiments, the reaction is conducted by reaction of from about 10 to about 20 moles of amine per mole of compound (16). This reaction is further conducted in organic reaction media such as those described above, preferably tetrahydrofuran, dioxane, dimethylsulfoxide, and so forth.

The C-5,7. di(chlorosulfonyl)xanthone-Z-carboxylic acid compound (16) is a novel intermediate useful as described above.

Certain of the compounds of the present invention can be prepared in accordance with the following reac tion sequence:

Scgucnco C 15 R -cu coon A Gri -R COORl' 5 ,7-dialkylxanthone-Z-carboxylic 15 I 16 Sequence C Continued 15 o 0011 o R -cn o 15 2 cu R coon l5 (19) cn -R, 20 l 0 n R -C R (A-m wherein each of halo, R, R and R is as above defined and R is lower alkyl.

With reference to the above reaction sequence, the acid compounds (20) are prepared as described above in Sequence A for compounds 1 6. Thereafter, compounds (20) are oxidized with chromic oxide in acetic acid, acetic anhydride to give the 5,7-di(loweralkanoyl) compounds (A2) which can be reduced to the 5;7-di-( l-hydroxyloweralkyl) compound (A-l) with sodium borohydride.

Certain of the compoundsof the present invention can be prepared in accordance with the following reaction sequence:

Sequence D Continued o R S coon R175 oon COOH l v qfi OOH 9 O 0 5 OOH 16 (B- l s 2 O wherein each of halo, R, R and R is as above de Certain of the compounds of the present invention fined; R is alkyl or alkoxy; and R is lower alkyl. 40 can be prepared in accordance with the following reaction sequence:

5.2 .llzllSL-LE 18 II 1) (26) R COOR O 19 SR COOR 00121 4 (2 7 halo COOR sulfinyl and sulfonyl compounds (B-l,2) and (B-3,4)

$894,049 19 a go sequence li' flontinued' 18 14 R @CQOR l, v R6 (Ii-3,4)

wherein each of halo, R, R and R is as above deeither directly or through the acid esters and fined, R is alkyl or -alkoxy; and- R islower alkyl. and as described above for compounds '5 6 A-3 With reference to the above reactionsequences D andA-4. and E, the 5-alkyl or alkoxy-7-lower alkylthio compounds (24) and corresponding 5-lower alkylthio-7- alkyl or alkoxy compounds (29) are prepared as de- Sequence D Alternatively, the compounds of formula (24) scribed above in Sequence A for compounds 1 6. wherein R is the methoxy group are converted to the compounds of formulas (B'-2) in accordance with the following reaction sequence:

Thereafter, the respective products are oxidized to the -Continued Sequence E wherein each of R", R R and R is as above defined; Alternatively, the compounds of formula (29) d h 1k 1 f wherein R is the methoxy group are converted to the an ls a lg er a y group contammg mm SIX 30 compounds of formulas (B'-4) in accordance with the to twelve carbon atoms. following reaction sequence:

wherein each of R', R, R and R is as above defined; and R"" is a higher alkyl group containing from six to twelve carbon atoms.

With reference to the above reaction sequences D and E, the 5-methoxy-7-lower alkylthio compounds (24') and 5-lower alkylthio-7-methoxy compounds (29') are converted to their corresponding S-hydroxy- 7-lower alkylthio compounds (61) and 5-lower alkylthio-7-hydroxy compounds (66) by treatment with hydriodic or hydrobromic acid in the presence of a suitable solvent, e.g., acetic anhydride, acetic acid or propionic acid.

The compounds of formulas 61) and (66) are then esterified with an alkyl halide, e.g., methyl iodide, ethyl bromide, and the like, in the presence of an organic sol- 20 I g ou coon halo

cook (2) bromododecane (dodecyl bromide), 2- bromododecane, and the like, in thepresence of an organic solvent, e.g., dimethylfonnamide, dimethylacetamide, acetone, and the like, and potassium carbonate, to obtain the S-higher alkoxy-T-lower alkylthio ester compounds (63) and 5-lower alkylthio-7-higher alkoxy ester compounds (68), respectively.

The compounds of formulas (63) and (68) are oxidized to the sulfinyl ester compounds of formulas (64) and (69), and sulfonyl ester compounds, formulas (6 5) and (70), as described above for the oxidation of the compounds of formula (6) to the compounds of formulas (A-3) and (A4). The compounds of-formulas (64) and (69) and (65) and (70) are then subjected to base hydrolysis, according to the method described above for the conversion of the compounds of formula (3) to the compounds of formula (4), thus yielding the 5- higher alkoxy-7-lower alkylsulfinyl acids of formula (B'-2) and 5-lower alkylsulfinylJ-higher alkoxy acids of formula (B'-4) and S-higher alkoxy-7-lower alkylsulfonyl acids of formula (B 2) and S-lower alkylsulfonyl- 7-higher alkoxy acids of formula (B'-4).

Certain of the compounds of the present invention can be prepared in accordance with the following reaction sequence:

Seguencc P coon R20 I coon Sequence F Continued O o Cl-iQ coon ll l J o 20 cooH hours. In the preferred embodiments, amounts of chlorosulfonic acid ranging from about 10 to about 25 moles per mole of starting compound are employed.

Thereafter, compounds (35) and (35) are converted to the sulfo compounds (8- l ,2) or the sulfamoyl compounds (B-3,4), such as described above for the preparation of compounds (A-5) and (A-6).

Certain of the compounds of the present invention can be prepared in accordance with the following reaction sequence:

Seguence G Sequence G Continued HCITO Acyl wherein each halo, R R R and R is as above defined, and Acyl is lower alkanoyl, preferably acetyl.

The compounds of formula (38 or 38") are reduced, such as with sodium borohydride, to prepare the COOlI corresponding l-hydroxylower alkyl compounds (41 and 42) which are acylated via conventional techniques and the acylated compounds are oxidized under Jones conditions to prepare the corresponding 5- or 7- (l-acyloxylower alkyl) xanthone-Z-carboxylic acid esters (43 and 44) which, when hydrolyzed under base conditions, gives the corresponding 5 or 7-(1- hydroxylower alkyl) xanthone-Zcarboxylic acids (18-12 and B3,4).

Compounds (38' and 38") can be oxidized, such as via the Jones oxidation, to give (39 and 40) which are hydrolyzed to give the 5- or 7-lower alkanoylxanthone- 2-carboxylic acids (B-l,2 and B-3,4).

lFurther methods by which certain of the compounds of the present invention can be prepared are as set forth in the following reaction sequences (H to K):

Sncrnqr c ll fiilllilliifi 3.5 n c11 I I crr R cu coon I on coon 1" l R "c21 I o RISCHZ ,coorr (EH3 ocH coon wherein each of R, R R and halo is as above defined and R is alkyl.

With reference to the above reaction sequences, Sequence H provides an alternate method by which compounds (5 useful as described in Sequence A, are prepared from compound (15) of Sequence B. Sequence l provides an alternate method by which compounds (16!), useful as described in Sequence B, are prepared from compound (15) of Sequence B through the xanthene sequence as described in Sequence G. Sequence J provides a method for preparing the 5-lower alkyl-7- hydroxy compounds (51) which are useful as described in Sequence B. Sequence J is also useful for preparing the corresponding 7-lower alkyl-S-hydroxy compounds, useful as described in Sequence B. Sequence K describes the preparation of the 5-methoxy-7-alkyl compounds (55) and is also useful for preparing the 5- alkyl-7-methoxy compounds, each of which is useful as described in Sequence C,

An alternative basic method by which certain of the compounds hereof can be prepared, as depicted above, is depicted as follows:

Sequence L Sequence L Continued C OOH wherein halo is as above defined and R at ortho or para or both positions is alkoxy.

With reference to Sequence L, an appropriate phenol (56) is treated with 1,3-dimethyl-4-halo- (preferably iodo) benzene (57), as described above, to prepare the corresponding l,3-dimethyl-4-phenyloxybenzene (58 This compound is then oxidized such as with potassium permanganate in aqueous t-butanol to give (59). This compound is then cyclized, as described above, to give the corresponding xanthone-Z-carboxylic acid (60) which can be treated variously as described above, to prepare certain of the compounds of the present invention.

The starting compounds for use in the present invention are known and can be prepared by processes known per se. Thus, the l,3-dicarbo(lower)alkoxy-4- halobenzene starting compounds (2) are conveniently prepared by oxidizing l,3-dimethylf4-halobenzene (4- halo-m-xylene) with potassium permanganate, as described above (58 59), followed by conventional esterification. The o,p-diloweralkylthiophenol compounds (l) are conveniently prepared by treating hydroxybenzoic acid with excess chlorosulfonic acid to give the corresponding o-hydroxy-m,m-di(chlorosulfonyl)-benzoic acid. This is reduced to the corresponding dimercapto compound with zinc and hydrogen chloride in acetic acid. The resultant compound is dialkylated with lower alkyl halide and potassium carbonate in dimethylformamide or with dialkylsulfate in aqueous sodium hydroxide to give 0-alkoxy-m,mdi( alkylthio )-benzoic acid. The latter is decarboxylated with heating in the presence of copper and quinoline and the resultant compound selectively hydrolyzed with pyridine hydrochloride or with hydrogen bromide in acetic acid to give the o,p-di(lower alkylthio phenol.

The o,p-dialkoxyphenol starting compounds, i.e. (7), are prepared by treating o,p-dihydroxyacetophenone with an appropriate alkyl halide and potassium carbon- -Villiger reaction and hydrolysis or by treating 1,3-

dialkylbenzene with nitric acid and sulfuric acid to give the l-nitro-2,4-dialkylbenzene, reduction of the latter with stannous chloride to the amine, treatment thereof with sodium nitrite in HCl followed by treatment with COOH COOH

dilute sulfuric acid and heat to give the o,pdialkylphenols.

The o-alkyl or -alkoxy-p-alkylthiophenol starting compounds, i.e., (21) wherein the R group contains from one to twelve carbon atoms, are conveniently prepared by treating an o-alkyl or -alkoxyphenol in which the alkyl or alkoxy group contains from one to twelve carbon atoms with chlorosulfonic acid in chloroform, followed by reduction with zinc l-lCl in acetic acid, followed by alkylation, all as described above (cf. preparation of l) or by treatment of an o-alkyl or -alkoxyphenol with dialkylsulfoxide and gaseous hydrogen chloride to give the corresponding 3-alkyl or -alkoxy-4- hydroxybenzene dialkylsulfonium chloride. The latter is heated to give the corresponding o-alkyl or -alkoxy-p-alkylthiophenol product.

The o-alkylphenol used as the starting material in preparing the o-alkyl compounds of e.g. formula (21) is prepared by treating phenol with an alkanoyl chloride (e.g. n-octanoyl chloride) to obtain the corresponding phenyl alkanoate (e.g. phenyl n-octanoate) which is then treated with aluminum chloride at C to obtain predominantly the o-alkanoyl phenol (e.g. on-octanoyl phenol) which is removed from any pisomer which may be present by steam distillation. The o-alkanoyl phenol (e.g. o-n-octanoyl phenol) is then reduced with zincamalgamhydrochloric acid to obtain the o-alkyl phenol (e.g. o-n-octyl phenol).

' The corresponding o'-alkylthio-p-alkyl or -alkoxyphenol starting compounds, i.e. (26) wherein the R group contains from one to twelve carbon atoms, are prepared by treating a palkyl or -alkoxyphenol in which the alkyl or alkoxy group contains from one to twelve carbon atoms with chlorosulfonic acid, followed by reduction, alkylation, all as described above, provides the desired compounds.

The p-alkyl phenol used as the starting material in preparing the p-alkyl compounds of e.g. formula (26) is prepared by treating phenol with an alkanoyl chloride (e.g. n-octanoyl chloride) to obtain the corresponding phenyl alkanoate (e.g. phenyl n-octanoate) which is then treated with aluminum chloride at 25C and in the presence of nitrobenzene to obtain predominantly p-alkanoyl phenol (e.g. p-n-octanoyl phenol) which is then purified by steam distillation to remove any o-isomer which may be present. The p-alkanoyl phenol (e.g. p-n-octanoyl phenol) is then reduced with lzinc amalgam-hydrochloric acid to obtain the p-alkyl phenol (e.g. p-n-octyl phenol).

The o-alkyl-p-alkoxyphenol starting compound, i.e. (47), is prepared by treating l-alkyl-3-alkoxybenzene under Friede l-Crafts conditions to give the corresponding acetyl compound followed by a Baeyer-Villiger reaction and hydrolysis, all as described above. Alternatively, p-alkoxyphenol starting compounds can be acetylated ortho to the hydroxy group and the resultant compound reduced. The o-alkoxy-p-alkylphenol starting compounds are prepared from o-alkoxyphenols via p-acetylation and reduction, all as described above.

The carboxylic acyl esters of the secondary hydroxy alkyl substituted compounds (ie. R'=carboxylic acyl and R carboxylic acyl of l-hydroxy alkyl) are pre pared as described above or by secondary alcohol esterification methods known per se. One such method involves treating the l-hydroxy alkyl products represented by Formulas A-l B-l,2 and B-3,4 of Sequences C and G with a carboxylic acid chloride or carboxylic acid anhydride in the presence of a base, preferably pyridine, at temperatures ranging from about 60 to about 90C and for a period of time ranging from about one to about two hours to give the corresponding secondary carboxylic acyloxy alkyl substituted xanthone- 2-carboxylic acid compound.

The alkyl and cycloalkyl ethers of the secondary hydroxyalkyl series (lR=alkyl, cycloalkyl and R =alkyl, cycloalkyl ethers of l-hydroxy alkyl) are prepared by treatment of the xanthone acid ester with the appropriate alkyl or cycloalkyl halide and sodium hydride in, e.g. dimethylformamide, followed by hydrolysis, as described above. The etherification reaction is conducted at from about 50 to about 80C and for from about one to about five hours.

The t-butoxy ethers are prepared by treating the alcohol with isobutene in the presence of boron trifluoride and phosphoric acid in, eg methylene chloride, at temperatures of from about to about 30C and for from 10 to about 24 hours, or more, followed by hydrolysis of the acid ester group, as described above.

The tetrahydrofuran-Z-yloxy and tetrahydropyran-2 yloxy ethers of the l-hydroxyalkyl compounds are prepared by treatment with dihydrofuran or dihydropyran in the presence of p-toluenesulfonic acid and organic reaction medium, e.g. benzene, at about room temperature up to reflux, for from about two to about five days, followed by hydrolysis of the acid ester, as described above.

The 4-alkoxytetrahydropyran-4-yloxy ethers are prepared by treatment of the alcohol with 4-alkoxy-5,6- dihydro-Zl-l-pyran, as described above for the preparation of the furanyl and pyranyl ethers, followed by acid ester hydrolysis. Treatment of the 4-alkoxytetrahydropyran-4-yloxy ether with aluminum chloride and lithium aluminum hydride in organic reaction medium affords the corresponding tetrahydropyran-4-yloxy ethers which are oxidized to give the corresponding ethers in the xanthone acid series. The latter can be directly prepared by treating the alcohol with 4-bromotetrahydropyran and base. See Harrison and Harrison, Compendium of Organic Synthetic Methods, Wiley-lnterscience, New York (1971) 129 and the references cited thereon.

The acid esters of the xanthone-2-carboxylic acids hereof are prepared as described above (eg 5 6) upon treatment of the acid with ethereal diazoalkane such as diazomethane and diazoethane or with the desired lower alkyl iodide in the presence of lithium carbonate at room temperature or with the desired lower alkanol in the presence ofa trace of sulfuric acid at reflux. The glycerol esters are prepared by treating the acid with thionyl chloride followed by treatment with a suitably protected ethylene glycol or propylene glycol (e.g. solketal) in pyridine, and hydrolyzing the protecting group of the ester thus formed with dilute acid. In

the sulfo series, the carboxylic acid esters are preferably prepared with the desired lower alkanol in the absence of acid catalyst.

The amides of the xanthone-Z-carboxylic acids hereof are prepared by treatment of the acids with thionyl chloride followed by treatment with anhydrous ammonia, alkyl, amine, dialkyl amine, dialkylaminoalkylamine, alkoxyalkylamine, or phenethylamine. in the lower alkyl sulfinyl series, the carboxylic acid amides are preferably prepared at the corresponding (lower alkylthio) stage followed by oxidation thereof, as described above.

The salts of the xanthone-Z-carboxylic acids hereof are prepared by treating the corresponding acids with pharmaceutically acceptable base. Representative salts derived from such pharmaceutically acceptable bases include the sodium, potassium, lithium, ammonia, calcium, magnesium, ferrous, ferric, zinc, manganous, aluminum, manganic, trimethylamine, triethylamine, tripropylamine, B-(dimethylamino)ethanol, triethanolamine, ,B-(diethylamino)ethanol, arginine, lysine, histidine, N-ethylpiperidine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methyl glucamine, theobromine, purines, piperazine, piperidine, polyamine resins, caffeine, procaine salts. The reaction is conducted in an aqueous solution, alone or in combination with an inert, water miscible organic solvent, at a temperature of from about 0C to about C, preferably at room temperature. Typical inert, water miscible organic solvents include methanol, ethanol, isopropanol, butanol, acetone, dioxane, or tetrahydrofuran. When divalent metal salts are prepared, such as the calcium salts or magnesium salts of the acids the free acid starting material is treated with about /2 molar equivalent of pharmaceutically acceptable base. When the aluminum salts of the acids are prepared, about /a molar equivalent of the pharmaceutically acceptable base are employed.

in the preferred embodiment of the present invention, the calcium salts and magnesium salts of the acids are prepared by treating the corresponding sodium or potassium salts of the acids with at least one molar equivalent of calcium chloride or magnesium chloride, respectively, in an aqueous solution, alone or in combination with an inert water miscible organic solvent, at a temperature of from about 20C to about 100C.

ln the preferred embodiment of the present invention, the aluminum salts of the acids are prepared by treating the acids with at least molar equivalent of an aluminum alkoxide, such as aluminum triethoxide, aluminum tripropoxide, and the like, in a hydrocarbon solvent, such as benzene, xylene, cyclohexane, and the like at a temperature of from about 20C to about 1 15C.

lln the sulfo series, use of one equivalent of base provides the sulfo acid monosalts; use of two equivalents provides the disalts.

in the present specification and claims, by the term lower alkyl is intended a lower alkyl group containing one to five carbon atoms including straight and branched chain groups and cyclic alkyl groups, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, sec-pentyl, t-pentyl, cyclopropyl, cyclobutyl, and cyclopentyl. By the term lower alkoxy" is intended the group 0- lower alkyl wherein lower alkyl is as defined above. The term alkyl as used herein is intended to include the lower alkyl groups as defined above and higher 

1. THE COMPOUND OF THE FORMULA:
 2. The compound according to claim 1 wherein R4 is methyl; 5,7-diacetylxanthone-2-carboxylic acid. 